<p>Immune checkpoint blockade (ICB) has shown limited efficacy in triple-negative breast cancer (TNBC), highlighting the need to elucidate mechanisms of immune evasion and identify novel therapeutic targets. Here, we identify MORC family CW-type zinc finger 2 (MORC2), an ATP-dependent chromatin remodeler, as a key epigenetic suppressor of antitumor immunity in TNBC. MORC2 is significantly upregulated in TNBC and correlates with an immunosuppressive tumor microenvironment and poor response to ICB. Genetic ablation of MORC2 inhibited tumor growth in immunocompetent but not immunodeficient mice, accompanied by enhanced CD8⁺ T cell cytotoxicity and M1-like macrophage polarization. Mechanistically, MORC2 cooperated with the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) to deposit histone H3 lysine 9 trimethylation (H3K9me3) repressive marks at transposable elements (TEs), thereby silencing their expression and suppressing viral mimicry through inhibition of endogenous nucleic acid-sensing pathways and interferon responses. Furthermore, SETDB1 methylated MORC2 at residues K234 and K643 to enhance its stability, thus establishing a positive feedback loop that reinforces epigenetic silencing. Importantly, therapeutic targeting of MORC2 using antisense oligonucleotides (ASOs) synergized with anti-PD-1 therapy to suppress tumor growth in mouse TNBC models. Clinically, MORC2 expression inversely correlated with CD8⁺ T cell infiltration and activation in human TNBC samples. Collectively, our findings establish MORC2 as a novel epigenetic immune checkpoint and highlight its therapeutic potential to overcome ICB resistance in TNBC.</p> Graphical Abstract <p></p>